Compounds as receptor modulators with therapeutic utility

ABSTRACT

The present invention relates to novel derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Non-Provisionalpatent application Ser. No. 13/300,537, filed Nov. 18, 2011, whichclaims the benefit of U.S. Provisional Application Ser. No. 61/416,081filed Nov. 22, 2010, which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to novel derivatives, processes forpreparing them, pharmaceutical compositions containing them and theiruse as pharmaceuticals, as modulators of sphingosine-1-phosphatereceptors. The invention relates specifically to the use of thesecompounds and their pharmaceutical compositions to treat disordersassociated with sphingosine-1-phosphate (S1P) receptor modulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

We have now discovered a group of novel compounds which are potent andselective sphingosine-1-phosphate modulators. As such, the compoundsdescribed herein are useful in treating a wide variety of disordersassociated with modulation of sphingosine-1-phosphate receptors. Theterm “modulator” as used herein, includes but is not limited to:receptor agonist, antagonist, inverse agonist, inverse antagonist,partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation. In one aspect, the invention provides acompound having Formula I or a pharmaceutically acceptable salt thereofor stereoisomeric forms thereof, or the geometrical isomers,enantiomers, diastereoisomers, tautomers, zwitterions andpharmaceutically acceptable salts thereof:

In one embodiment of the invention, there are provided compounds havingthe Formula I below and pharmaceutically accepted salts thereof, itsenantiomers, diastereoisomers, hydrates, solvates, crystal forms andindividual isomers, tautomers or a pharmaceutically acceptable saltthereof,

wherein:R¹ is N or C—R⁹;R² is substituted or unsubstituted aromatic heterocycle, C₅₋₈cycloalkenyl or C₆₋₁₀ aryl;R³ is O, N—R¹⁰, CH—R¹¹, S, —CR¹²═CR¹³—, —C≡C— or —C(O)—;R⁴ is H, C₅₋₈ cycloalkenyl, C₃₋₈ cycloalkyl or substituted orunsubstituted C₆₋₁₀ aryl;R⁵ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl or hydroxyl;R⁶ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl or hydroxyl;a is 0, 1, 2, 3 or 4;b is 0, 1, 2, 3 or 4;L is CHR⁷, O, S, NR⁸ or —C(O)—;R⁷ is H, C₁₋₃ alkyl, —OC₁₋₃ alkyl, halogen, hydroxyl or NR⁹R¹⁰;R⁸ is H or C₁₋₃ alkyl;R⁹ is H, halogen or C₁₋₃ alkyl;R¹⁰ is H or C₁₋₃ alkyl;R¹¹ is H or C₁₋₃ alkyl;R¹² is H or C₁₋₃ alkyl;R¹³ is H or C₁₋₃ alkyl;Q¹ is —CR¹⁴R¹⁵—;R¹⁴ is H, halogen, or C₁₋₃ alkyl;R¹⁵ is H, halogen, or C₁₋₃ alkyl;m is 0, 1, 2 or 3;

-   -   “*” represents the point of attachment to the rest of the        molecule;        R¹⁸ is NR⁹, O, or S;        Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl, H, —

with the proviso that when R³ is O, N—R¹⁰, S, —CR¹²═CR¹³—, —C≡C— or—C(O)— and b is 0 or 1 then L is not O, S, NR⁸ or —C(O)—.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is N or C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycleor C₅₋₈ cycloalkenyl;

R³ is O, N—R¹⁰, CH—R¹¹, S;

R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;

R⁵ is H, or halogen;

R⁶ is H or halogen;

R⁸ is H or C₁₋₃ alkyl;

R⁹ is H or C₁₋₃ alkyl;

R¹⁰ is H or C₁₋₃ alkyl;

R¹¹ is H or C₁₋₃ alkyl;

a is 0, 1, 2, 3 or 4;

b is 0, 1, 2, 3 or 4;

L is CH₂;

m is 0;

T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is N or C—R⁹;

R² is furan, 2-furyl and 3-furyl derivatives; thiophene, 2-thienyl and3-thienyl derivatives; pyrrole, oxazole, thiazole, pyrrolidine,pyrroline, imidazole, pyrazole, pyrazoline, isoxazole, isothiazole,pyrazolidine, imidazoline, thiazoline, oxazoline, dihydrothiophene,dihydrofuran, tetrazole, triazole, oxadiazole, 1,2,5-oxadiazole,thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrrolidinone,pyrrol-2(3H)-one, imidazolidin-2-one, or 1,2,4-triazol-5(4H)-one and thelike 5-membered heterocyclic rings;R³ is O, N—R¹⁰, CH—R¹¹, S;R⁴ is phenyl with ortho, meta and para substitution with groups such as:halogens fluoro, chloro and bromo; short chain alkyls methyl, ethyl,propyl, isopropyl and other, methoxy, trifluoromethoxy, trifluoromethyland perfluorinated short chain alkyl groups;R⁵ is H, or halogen;R⁶ is H or halogen;R⁸ is H or C₁₋₃ alkyl;R⁹ is H or C₁₋₃ alkyl;R¹⁰ is H or C₁₋₃ alkyl;R¹¹ is H or C₁₋₃ alkyl;a is 0, 1, 2, 3 or 4;b is 0, 1, 2, 3 or 4;L is CH₂;m is 0;T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycleor C₅₋₈ cycloalkenyl;

R³ is O, N—R¹⁰, CH—R¹¹, S;

R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;

R⁵ is H, or halogen;

R⁶ is H or halogen;

R⁸ is H or C₁₋₃ alkyl;

R⁹ is H or C₁₋₃ alkyl;

R¹⁰ is H or C₁₋₃ alkyl;

R¹¹ is H or C₁₋₃ alkyl;

a is 0, 1, 2, 3 or 4;

b is 0, 1, 2, 3 or 4;

L is CH₂;

m is 0;

T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H, Cl, Br or F;

R⁶ is H, Cl, Br or F;

a is 1, 2, or 3;

b is 1, 2, or 3;

L is CHR⁷;

R⁷ is H or C₁₋₃ alkyl;

m is 0;

T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H, Cl, Br or F;

R⁶ is H, Cl, Br or F;

a is 1, 2, or 3;

b is 1, 2, or 3;

L is CHR⁷;

R⁷ is H or C₁₋₃ alkyl;

m is 0;

T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H or F;

R⁶ is H or F;

R⁸ is H or C₁₋₃ alkyl;

R⁹ is H or C₁₋₃ alkyl;

a is 1, 2, or 3;

b is 1, 2, or 3;

L is CH₂;

m is 0;

T is —NH-Q²;

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H or F;

R⁶ is H or F;

R⁹ is H;

a is 2;

b is 2;

L is CH₂;

m is 0;

T is —NH-Q²;

Q² is —C₁₋₆ alkyl,

“*” represents the point of attachment to the rest of the molecule.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹ or N;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;

a is 0, 1, 2, 3 or 4;

b is 0, 1, 2, 3 or 4;

R⁵ is H, or F,

R⁶ is H, or F,

R⁹ is H or C₁₋₃ alkyl;

L is CH₂;

Q¹ is —CR¹⁴R¹⁵—;

R¹⁴ is H;

R¹⁵ is H;

m is 2;

-   -   “*” represents the point of attachment to the rest of the        molecule;        R¹⁸ is NR⁹;        Q² is —OPO₃H₂, —OH, carboxylic acid, —PO₃H₂, H, —C₁₋₆ alkyl,        —P(O)MeOH or —P(O)(H)OH.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹ or N;

R² is a five-membered substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H, or F;

R⁶ is H or F;

a is 1, 2, or 3;

b is 1, 2, or 3;

R⁹ is H or C₁₋₃ alkyl;

L is CH₂;

Q¹ is —CR¹⁴R¹⁵—;

R¹⁴ is H;

R¹⁵ is H;

m is 2;

“*” represents the point of attachment to the rest of the molecule;Q² is —OPO₃H₂, —OH, carboxylic acid, —PO₃H₂, H, —C₁₋₆ alkyl, —P(O)MeOHor —P(O)(H)OH.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H or F;

R⁶ is H or F;

R⁹ is H;

a is 2;

b is 2;

L is CH₂;

Q¹ is —CR¹⁴R¹⁵—;

R¹⁴ is H;

R¹⁵ is H;

m is 2;

-   -   “*” represents the point of attachment to the rest of the        molecule;        Q² is —OPO₃H₂, —OH, carboxylic acid, —PO₃H₂, H, —C₁₋₆ alkyl,        —P(O)MeOH or —P(O)(H)OH.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is N or C—R⁹;

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H, or F;

R⁶ is H, or F;

a is 1, 2, or 3;

b is 1, 2, or 3;

L is CH₂;

R⁹ is H or C₁₋₃ alkyl;

m is 0;

-   -   “*” represents the point of attachment to the rest of the        molecule;        R¹⁸ is NR⁹;        Q² is —OPO₃H₂, —OH, carboxylic acid, —PO₃H₂, H, —C₁₋₆ alkyl,        —P(O)MeOH or —P(O)(H)OH.

In another aspect, the invention provides a compound having Formula Iwherein:

R¹ is C—R⁹

R² is a five-membered aromatic substituted or unsubstituted heterocycle;

R³ is O;

R⁴ is substituted or unsubstituted phenyl;

R⁵ is H, or F;

R⁶ is H, or F;

R⁹ is H;

a is 2;

b is 2;

L is CH₂;

m is 0;

-   -   “*” represents the point of attachment to the rest of the        molecule;        R¹⁸ is NR⁹;        Q² is —OPO₃H₂, —OH, carboxylic acid, —PO₃H₂, H, —C₁₋₆ alkyl,        —P(O)MeOH or —P(O)(H)OH.

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is N or C—R⁹;    -   R² is substituted or unsubstituted heterocycle, C₆₋₈        cycloalkenyl or C₆₋₁₀ aryl;    -   R³ is O, N—R¹⁰, CH—R¹¹, S, —CR¹²═CR¹³—, —C≡C— or —C(O)—;    -   R⁴ is H, C₆₋₈ cycloalkenyl, C₃₋₈ cycloalkyl or substituted or        unsubstituted C₆₋₁₀ aryl;    -   R⁵ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl or hydroxyl;    -   R⁶ is H, halogen, —OC₁₋₃ alkyl, C₁₋₃ alkyl or hydroxyl;    -   a is 0, 1, 2, 3 or 4;    -   b is 0, 1, 2, 3 or 4;    -   L is CHR⁷, O, S, NR⁸ or —C(O)—;    -   R⁷ is H, C₁₋₃ alkyl, —OC₁₋₃ alkyl, halogen, hydroxyl or NR⁹R¹⁰;    -   R⁸ is H or C₁₋₃ alkyl;    -   R⁹ is H, halogen or C₁₋₃ alkyl;    -   R¹⁰ is H or C₁₋₃ alkyl;    -   R¹¹ is H or C₁₋₃ alkyl;    -   R¹² is H or C₁₋₃ alkyl;    -   R¹³ is H or C₁₋₃ alkyl;    -   Q¹ is —CR¹⁴R¹⁵—;    -   R¹⁴ is H, halogen, or C₁₋₃ alkyl;    -   R¹⁵ is H, halogen, or C₁₋₃ alkyl;    -   m is 0, 1, 2 or 3;

-   -   -   “*” represents the point of attachment to the rest of the            molecule;

    -   R¹⁸ is NR⁹, O, or S;

    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

-   -   with the proviso that when R³ is O, N—R¹⁰, S, —CR¹²═CR¹³—, —C≡C—        or —C(O)— and b is 0 or 1 then L is not O, S, NR⁸ or —C(O)—.

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is a five-membered substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 1 or 2;    -   b is 1 or 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H or C₁₋₃ alkyl;    -   Q¹ is —CR¹⁴R¹⁵—;    -   R¹⁴ is H;    -   R¹⁵ is H;    -   m is 2;

-   -   -   “*” represents the point of attachment to the rest of the            molecule;

    -   R¹⁸ is NR⁹;

    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl, H, —P(O)MeOH, —P(O)(H)OH, —OH.

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is a five-membered substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 1 or 2;    -   b is 1 or 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H or C₁₋₃ alkyl;    -   Q¹ is —CR¹⁴R¹⁵—;    -   R¹⁴ is H;    -   R¹⁵ is H;    -   m is 2;    -   T is —NH-Q²,

-   -   -   “*” represents the point of attachment to the rest of the            molecule;

    -   R¹⁸ is NR⁹;

    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl, H, —P(O)MeOH, —P(O)(H)OH, —OH.

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is a five-membered substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted C₆₋₁₀ aryl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 1 or 2;    -   b is 1 or 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H or C₁₋₃ alkyl;    -   Q¹ is —CR¹⁴R¹⁵—;    -   R¹⁴ is H;    -   R¹⁵ is H;    -   m is 2;

-   -   -   “*” represents the point of attachment to the rest of the            molecule;

    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl, H, —P(O)MeOH, —P(O)(H)OH, —OH.

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted phenyl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 2;    -   b is 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H;    -   m is 0;    -   T is —NH-Q²,        -   “*” represents the point of attachment to the rest of the            molecule;    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted phenyl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 2;    -   b is 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H;    -   m is 0;    -   T is —NH-Q²,        -   “*” represents the point of attachment to the rest of the            molecule;    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted phenyl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 2;    -   b is 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H;    -   m is 0;    -   T is —NH-Q²,        -   “*” represents the point of attachment to the rest of the            molecule;    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted phenyl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 2;    -   b is 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H;    -   m is 0;    -   T is —NH-Q²,        -   “*” represents the point of attachment to the rest of the            molecule;    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

In another aspect, the invention provides a compound having Formula Iwherein:

-   -   R¹ is C—R⁹;    -   R² is substituted or unsubstituted heterocycle;    -   R³ is O;    -   R⁴ is substituted or unsubstituted phenyl;    -   R⁵ is H or halogen;    -   R⁶ is H or halogen;    -   a is 2;    -   b is 2;    -   L is CHR⁷;    -   R⁷ is H;    -   R⁹ is H;    -   m is 0;    -   T is —NH-Q²,        -   “*” represents the point of attachment to the rest of the            molecule;    -   Q² is the same or independently —OPO₃H₂, carboxylic acid,        —PO₃H₂, —C₁₋₆ alkyl,

The term “alkyl”, as used herein, refers to saturated, monovalenthydrocarbon moieties having linear or branched moieties or combinationsthereof and containing 1 to 6 carbon atoms. One methylene (—CH₂—) group,of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₆ cycloalkyl. Alkylgroups can be substituted by halogen, amino, hydroxyl, cycloalkyl,amino, non-aromatic heterocycles, carboxylic acid, phosphonic acidgroups, sulphonic acid groups, phosphoric acid.

The term “short chain alkyl” as used herein, refers to saturatedmonovalent linear or branched moieties containing 1 to 3 carbon atoms.

The term perfluorinated short chain alkyl groups as used herein, refersto but CF₃—CF₂—, CF₃, (CF₃)₂—CH—, CF₃—(CF₃)₂—.

The term “alkylene”, as used herein, refers to saturated, divalenthydrocarbon moieties having linear or branched moieties or combinationsthereof and containing 1 to 6 carbon atoms. One methylene (—CH₂—) groupof the alkylene can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by 1 to 3 C₁₋₃ alkyl groups or 1 or 2halogens.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 5 to 8 carbon atoms, derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be substituted by C₁₋₃ alkylgroups or halogens.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₃ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which is aromatic or non-aromatic, saturated or non-saturated andcontaining at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted by hydroxyl,C₁₋₃ alkyl or halogens. Examples of aromatic heterocycles are, but notlimited to: furan, 2-furyl and 3-furyl derivatives; thiophene,2-thienyl, 3-thienyl derivatives; pyrrole, oxazole, thiazole, imidazole,pyrazole, isoxazole, isothiazole, tetrazole, triazole, oxadiazole,1,2,5-oxadiazole, thiadiazole, 1,2,3-triazole, 1,2,4-triazole.

Examples of non-aromatic heterocycles are, but not limited to:pyrrolidine, pyrroline, pyrazoline, pyrazolidine, imidazoline,thiazoline, oxazoline, dihydrothiophene, dihydrofuran, pyrrolidinone,pyrrol-2(3H)-one, imidazolidin-2-one, or 1,2,4-triazol-5(4H)-one.

Usually, in the present case, heterocyclic groups are 5 or 6 memberedrings including but not limited to: 1-substituted-1H-1,2,4-triazole,1-substituted-azetidine-3-CO₂H, 4-linked-indole,6-methyl-5-linked-indazole or 6-hydro-5-linked-indazole. Some preferredheterocycles at the R² position include the following: furan, 2-furyland 3-furyl derivatives; thiophene, 2-thienyl and 3-thienyl derivatives;pyrrole, oxazole, thiazole, pyrrolidine, pyrroline, imidazole, pyrazole,pyrazoline, isoxazole, isothiazole, pyrazolidine, imidazoline,thiazoline, oxazoline, dihydrothiophene, dihydrofuran, tetrazole,triazole, oxadiazole, 1,2,5-oxadiazole, thiadiazole, 1,2,3-triazole,1,2,4-triazole, pyrrolidinone, pyrrol-2(3H)-one, imidazolidin-2-one, or1,2,4-triazol-5(4H)-one and the like 5-membered heterocyclic rings.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl is optionally substituted byhalogen atoms or by C₁₋₃ alkyl groups. Preferred aryl groups at the R⁴position include: phenyl with ortho, meta and para substitution withgroups such as: halogens fluoro, chloro and bromo; short chain alkylsmethyl, ethyl, propyl, isopropyl and other, methoxy, trifluoromethoxy,trifluoromethyl and perfluorinated short chain alkyl groups.

The group of formula “—CR¹²═CR¹³—”, as used herein, represents analkenyl radical.

The group of formula “—C≡C—”, as used herein, represents an alkynylradical.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “boronic acid”, as used herein, represents a group of formula“—B(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   (2R)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyl    dihydrogen phosphate;-   (2S)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyl    dihydrogen phosphate;-   2-amino-3-hydroxy-2-methyl-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;-   2-amino-3-hydroxy-2-methyl-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;-   (2S)-2-amino-3-({3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyl    dihydrogen phosphate;-   (2S)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyl    dihydrogen phosphate;-   2-amino-N-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;-   2-amino-3-hydroxy-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;-   2-amino-3-({3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyl    dihydrogen phosphate;-   2-amino-3-{[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]amino}-3-oxopropyl    dihydrogen phosphate;-   2-amino-3-({3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyl    dihydrogen phosphate;-   2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}amino)propyl    dihydrogen phosphate;-   2-amino-3-({6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}amino)-3-oxopropyl    dihydrogen phosphate;-   2-amino-N-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;-   2-amino-N-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;-   2-amino-N-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;-   2-amino-3-hydroxy-N-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}propanamide;-   2-amino-N-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-3-hydroxypropanamide;-   2-amino-4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyl    dihydrogen phosphate;-   2-amino-2-(hydroxymethyl)-4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}butyl    dihydrogen phosphate;-   2-amino-4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyl    dihydrogen phosphate;-   2-amino-4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-2-(hydroxymethyl)butyl    dihydrogen phosphate;-   2-amino-4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyl    dihydrogen phosphate;-   2-amino-2-(hydroxymethyl)-4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}butyl    dihydrogen phosphate;-   2-amino-4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-2-(hydroxymethyl)butyl    dihydrogen phosphate;-   2-amino-2-(2-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;-   2-amino-2-(2-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}ethyl)propane-1,3-diol;-   2-amino-2-(2-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;-   2-amino-2-{2-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]ethyl}propane-1,3-diol;-   2-amino-2-(2-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;-   2-amino-2-(2-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}ethyl)propane-1,3-diol;-   2-amino-2-(2-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}ethyl)propane-1,3-diol;-   2-amino-2-(4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-(4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-{4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-1H-imidazol-2-yl}ethyl    dihydrogen phosphate;-   2-amino-2-(4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-(4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-1H-imidazol-2-yl)ethyl    dihydrogen phosphate;-   2-amino-2-(4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;-   2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}-1H-imidazol-2-yl)ethanol;-   2-amino-2-(4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;-   2-amino-2-{4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-1H-imidazol-2-yl}ethanol;-   2-amino-2-(4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;-   2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}-1H-imidazol-2-yl)ethanol;-   2-amino-2-(4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-1H-imidazol-2-yl)ethanol.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicacid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid and the like; or an organic acid such asfor example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid,malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and thelike (Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta—Zurich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically. Compounds according to thepresent invention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation: not limited to the treatment of diabetic retinopathy,other retinal degenerative conditions, dry eye, angiogenesis and wounds.

Therapeutic utilities of S1P modulators are ocular diseases, such as butnot limited to: wet and dry age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity, retinal edema, geographicatrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensiveretinopathy, ocular ischemic syndrome, prevention ofinflammation-induced fibrosis in the back of the eye, various ocularinflammatory diseases including uveitis, scleritis, keratitis, andretinal vasculitis; or systemic vascular barrier related diseases suchas but not limited to: various inflammatory diseases, including acutelung injury, its prevention, sepsis, tumor metastasis, atherosclerosis,pulmonary edemas, and ventilation-induced lung injury; or autoimmunediseases and immunosuppression such as but not limited to: rheumatoidarthritis, Crohn's disease, Graves' disease, inflammatory bowel disease,multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis,antoimmune uveitis, renal ischemia/perfusion injury, contacthypersensitivity, atopic dermititis, and organ transplantation; orallergies and other inflammatory diseases such as but not limited to:urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection such as but not limited to: ischemia reperfusioninjury and atherosclerosis; or wound healing such as but not limited to:scar-free healing of wounds from cosmetic skin surgery, ocular surgery,GI surgery, general surgery, oral injuries, various mechanical, heat andburn injuries, prevention and treatment of photoaging and skin ageing,and prevention of radiation-induced injuries; or bone formation such asbut not limited to: treatment of osteoporosis and various bone fracturesincluding hip and ankles; or anti-nociceptive activity such as but notlimited to: visceral pain, pain associated with diabetic neuropathy,rheumatoid arthritis, chronic knee and joint pain, tendonitis,osteoarthritis, neuropathic pains; or central nervous system neuronalactivity in Alzheimer's disease, age-related neuronal injuries; or inorgan transplant such as renal, corneal, cardiac or adipose tissuetransplant; inflammatory skin diseases, scleroderma, dermatomyositis,atopic dermatitis, lupus erythematosus, epidermolysis bullosa, andbullous pemphigold. Topical use of S1P (sphingosine) compounds is of usein the treatment of various acne diseases, acne vulgaris, and rosacea.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular disease, wet and dry age-relatedmacular degeneration, diabetic retinopathy, retinopathy of prematurity,retinal edema, geographic atrophy, glaucomatous optic neuropathy,chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome,prevention of inflammation-induced fibrosis in the back of the eye,various ocular inflammatory diseases including uveitis, scleritis,keratitis, and retinal vasculitis; or systemic vascular barrier relateddiseases, various inflammatory diseases, including acute lung injury,its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonaryedemas, and ventilation-induced lung injury; or autoimmune diseases andimmunosuppression, rheumatoid arthritis, Crohn's disease, Graves'disease, inflammatory bowel disease, multiple sclerosis, Myastheniagravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renalischemia/perfusion injury, contact hypersensitivity, atopic dermititis,and organ transplantation; or allergies and other inflammatory diseases,urticaria, bronchial asthma, and other airway inflammations includingpulmonary emphysema and chronic obstructive pulmonary diseases; orcardiac protection, ischemia reperfusion injury and atherosclerosis; orwound healing, scar-free healing of wounds from cosmetic skin surgery,ocular surgery, GI surgery, general surgery, oral injuries, variousmechanical, heat and burn injuries, prevention and treatment ofphotoaging and skin ageing, and prevention of radiation-inducedinjuries; or bone formation, treatment of osteoporosis and various bonefractures including hip and ankles; or anti-nociceptive activity,visceral pain, pain associated with diabetic neuropathy, rheumatoidarthritis, chronic knee and joint pain, tendonitis, osteoarthritis,neuropathic pains; or central nervous system neuronal activity inAlzheimer's disease, age-related neuronal injuries; or in organtransplant such as renal, corneal, cardiac or adipose tissue transplant;inflammatory skin diseases, scleroderma, dermatomyositis, atopicdermatitis, lupus erythematosus, epidermolysis bullosa, and bullouspemphigold.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made. Those skilled in theart will be able to routinely modify and/or adapt the following schemesto synthesize any compounds of the invention covered by Formula I.

In Scheme 1, aryl amines or aryl amine derivatives or precursors reactwith functionalized compounds such as halogenated or hydroxylatedcompounds in the presence of reagents that promote alkylation as knownto synthetic chemists to give the corresponding ether intermediate. Thisintermediate from the last step is coupled with the boronic acid or thestannate, generally involving a metal catalyst under appropriateconditions with an R² group to give the corresponding intermediate. Theprevious intermediate from the coupling procedure may be converted to anaryl amine as required for the next step by deprotection or reductionmethods. The intermediate from the previous step reacts to form an amideunder conditions that may employ carboxylic acids and the like to givean intermediate of Formula I. This intermediate from the last step isreacted with appropriate reagents to promote phosphorylation and yield aderivative of Formula I as a Compound of the invention upon removal ofany required protecting groups.

In Scheme II, aryl amines/amine precursors that may contain a halogensuch as a bromine atom, react with functionalized compounds such as ahalogenated or hydroxylated compound, in the presence of reagents thatpromote alkylation well known to synthetic chemists to give thecorresponding ether intermediate. This intermediate from the last stepis coupled with the boronic acid or the stannate involving a metalcatalyst under appropriate conditions with an R² group (shown as a2-furyl derivative below) to give the corresponding intermediate. Theintermediate from the previous step may be converted to an aryl amine asrequired for the next step by deprotection or reduction methods. Thisaryl amine from the last step reacts to form an amide under conditionsthat may employ carboxylic acids and the like to give an intermediate ofFormula I. This intermediate is reacted with appropriate reagents topromote phosphorylation and yield a derivative of Formula I as aCompound of the invention upon removal of any required protectinggroups.

In Scheme III, elaborated aryl bromides, are obtained according toapplication of appropriate synthetic preparation, may react withcompounds in the presence of reagents that promote alkylation. Thisintermediate from the last step that contains the R³ group (representingan —O—, —S— —NH—, —CH₂—) or other group is coupled with the boronic acidor the stannate under appropriate conditions with an R² group to givethe corresponding intermediate. This intermediate from the previous stepis reacted with appropriate reagents to promote phosphorylation andyield a derivative of Formula I as a Compound of the invention uponremoval of any required protecting groups.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts lowered lymphocyte count after 24 hours (<1 number oflymphocytes 10³/μL blood) by Compound 4.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8, and someintermediates' and reagents' names used in the examples were generatedwith software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000from MDL ISIS Draw 2.5 SP1 or from a commercial supplier catalog such asSigma-Aldrich.

In general, characterization of the compounds is performed using NMRspectra which were recorded on 300 and/or 600 MHz Varian and acquired atroom temperature. Chemical shifts were given in ppm referenced either tointernal TMS or to the solvent signal. Coupling constant J reported inHz, hertz.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures. Usually the compounds of theinvention were purified by column chromatography (Auto-column) on aTeledyne-ISCO CombiFlash with a silica gel column, unless notedotherwise.

The following abbreviations are used in the examples:

s, m, h, d second, minute, hour, day CH₃CN acetonitrile PSI pound persquare inch DCM dichloromethane DMF N,N-dimethylformamide NaOH sodiumhydroxide MeOH methanol CD₃OD deuterated methanol NH₃ ammonia HClhydrochloric acid Na₂SO₄ sodium sulfate RT or rt room temperature MgSO₄magnesium sulfate EtOAc ethyl acetate CDCl₃ deuterated chloroformDMSO-d₆ deuterated dimethyl sulfoxide Auto-column automated flash liquidchromatography TFA trifluoroacetic acid THF tetrahydrofuran M molarPdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) chloride AcOH aceticacid K₂CO₃ potassium carbonate NaCl sodium chloride CHCl₃ chloroformHATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate)

Those skilled in the art will be routinely able to modify and/or adaptthe following procedures to synthesize any compound of the inventioncovered by Formula I.

Example 1 Intermediate 1 2-bromo-4-nitro-1-((5-phenylpentyl)oxy)benzene

A mixture of 2-bromo-4-nitrophenol (CAS 5847-59-6) (2.05 g, 9.4 mmol),(5-bromopentyl)benzene (CAS 14469-83-1) (2.41 g, 10.6 mmol) and K₂CO₃(3.5 g, 19.1 mmol) was dissolved in DMF (20 mL). The reaction mixturewas heated at 100° C. for ˜18 h. The mixture was diluted withhexanes:EtOAc (1:1) (˜200 mL) and washed with H₂O (3×). The organicsolution was dried over MgSO₄, filtered, and concentrated onto silicagel under vacuum. Auto-column (9.5 hexanes: 0.5 EtOAc) gave Intermediate1 as a white solid 1.91 g (56%).

Example 2 Intermediate 22-[5-nitro-2-(5-phenyl-pentyloxy)-phenyl]-thiophene

A mixture of Intermediate 1 (1.91 g, 5.25 mmol),tributyl-thiophen-2-yl-stannane (CAS 54663-78-4) (3.4 mL, 10.7 mmol) andPdCl₂(PPh₃)₂ (0.55 g, 15 mol %) in DMF (12 mL) was reacted under MWI at160° C. for 15 m. The mixture was cooled to rt and diluted withhexanes:EtOAc (1:1, 200 mL). The mixture was washed with water (3×),dried over MgSO₄, filtered and concentrated onto silica gel undervacuum. Auto-column (9.5 hexanes: 0.5 EtOAc) produced Intermediate 2 asan orange solid, 1.10 g (57%).

Example 3 Intermediate 34-(5-phenyl-pentyloxy)-3-thiophen-2-yl-phenylamine

A mixture of iron chips (0.62 g, 11.1 mmol), NH₄Cl (0.88 g, 16.4 mmol),water (3.3 mL), and ethanol (10 mL) were heated to reflux for 15 m. Thismixture was transferred into a solution of Intermediate 2 (1.0 g, 2.72mmol) in EtOH (8 mL). The resulting mixture was heated to reflux for 5h. The mixture was filtered, washed with EtOAc and partitioned betweenEtOAc and water. The organic layers were dried over MgSO₄, filtered andconcentrated onto silica gel. Auto-column (7 hexane: 3 EtOAc) gaveIntermediate 3, as a tan solid 0.55 g (60%).

Example 4 Intermediate 4 (R)-tert-butyl(3-hydroxy-2-methyl-1-oxo-1-((4-((5-phenylpentyl)oxy)-3-(thiophen-2-yl)phenyl)amino)propan-2-yl)carbamate

Intermediate 3 (0.30 g, 0.89 mmol), Boc-D-serine (CAS 84311-18-2) (0.25g, 1.11 mmol), HATU (CAS 148893-10-1) (0.51 g, 1.34 mmol),diisopropylethylamine (CAS 7087-68-5) (0.46 mL) in DMF (20 mL) wasreacted at rt for ˜18 h. After an aqueous workup and extraction with(hexanes:EtOAc) the organic layers were combined and concentrated ontosilica gel. Auto-column (3% MeOH in CH₂Cl₂) gave Intermediate 4 0.28 g,(58%).

Example 5 Intermediate 52-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate

Intermediate 4 (0.28 g, 5.20 mmol), tetrazole (7.0 mL, 3.15 mmol; 0.45 Min CH₃CN), and di-tert-butyl diisopropyl-phosphoramidite (0.65 mL, 2.06mmol) in DMF (5 mL) were stirred at RT for ˜18 h. Hydrogen peroxide 35%(0.19 mL, 2.2 mmol) excess was added at 0° C. and the mixture was warmedto RT and stirred for 1 h. The solvent was removed under vacuum and theresidue was quenched with sat. Na₂S₂O₃ (10% aq) and extracted withEtOAc. The organic layers were dried over MgSO₄, filtered, concentratedonto silica gel under vacuum. Auto-column (6 hexanes: 4 EtOAc) gaveIntermediate 5 as a white solid 0.27 g (71%).

Example 6 Compound 1(2R)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate

Intermediate 5 was dissolved in CH₂Cl₂ and reacted with HCl in dioxane.The mixture was reacted for ˜18 h at rt. The solvent was removed undervacuum and the crude material was titurated several times with diethylether to give Compound 1 as a solid, ˜160 mg.

(300 MHz, CD₃OD): δ 7.89 (d, J=2.4, 1H), 7.50-7.44 (m, 2H), 7.37 (d,J=5.4, 1H), 7.26-7.21 (m, 2H), 7.17-7.13 (m, 3H), 7.06-7.00 (m, 2H),4.42 (dd, J=5.1, 11.4, 1H), 4.20 (dd, J=4.8, 11.7, 1H), 4.08 (t, J=6.3,2H), 2.63 (t, J=7.2, 2H), 1.91-1.84 (m, 2H), 1.74-1.65 (m, 2H), 1.68 (s,3H), 1.62-1.53 (m, 2H).

Compound 2 prepared from the corresponding starting materials in asimilar manner to the procedure described for Compound 1. The resultsare tabulated below in Table 1.

TABLE 1 Compound 2 IUPAC Name(2S)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyl dihydrogen phosphate Structure

¹H NMR δ (ppm) (600 MHz, CD₃OD/CDCl₃) δ: 7.91 (d, J = 2.4, 1H), 7.51 (d,J = 3.0, 1H), 7.45 (dd, J = 2.4, 9.0, 1H), 7.33 (d, J = 4.8, 1H), 7.25(t, J = 7.8, 2H), 7.18-7.14 (m, 3H), 7.06 (t, J = 4.8, 1H), 6.95 (d, J =9.0, 1H), 4.27 (dd, J = 5.4, 10.8, 1H), 4.07 (t, J = 6.6, 2H), 3.96 (dd,J = 5.4, 9.6, 1H), 2.65 (t, J = 7.8, 2H), 1.93-1.89 (m, 2H), 1.74-1.68(m, 2H), 1.61-1.57 (m, 2H), 1.50 (s, 3H). Intermediate(s) 1, 2 and 3starting Boc-L-serine material(s)

Example 7 Intermediate 7 2-(2-(benzyloxy)-5-nitrophenylfuran

Intermediate 7 was prepared from Intermediate 1 andtributyl-2-furanyl-stannane, in a similar manner to the proceduredescribed in Example 2 for Intermediate 2.

Example 8 Intermediate 8 3-furan-2-yl-4-(5-phenyl-pentyloxy)-phenylamine

Intermediate 8 was prepared from Intermediate 7 in a similar manner tothe procedure described in Example 3 for Intermediate 3.

Example 9 Intermediate 9{(S)-1-[3-furan-2-yl-4-(5-phenyl-pentyloxy)-phenylcarbamoyl]-2-hydroxy-ethyl}-carbamicacid benzyl ester

Intermediate 8 (0.98 g, 3.05 mmol), N-carbobenzoxy-L-serine (0.82 g,3.36 mmol), HATU (2.0 g, 5.1 mmol), and diisopropylethylamine (1.8 mL,10.3 mmol) in DMF (30 mL) was allowed to react for ˜18 h at RT. Autocolumn (6 hexanes:4 EtOAc) gave a crude Intermediate 9 as a yellowsolid, 1.32 g (80%).

Example 10 Intermediate 10 benzyl[2-({3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-1-{[(3-oxido-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)oxy]methyl}-2-oxoethyl]carbamate

Intermediate 9 (1.32 g, 2.43 mmol), tetrazole (16.2 mL, 7.29 mmol; 0.45M in CH₃CN), and3-(diethylamino)-1,5-dihydro-2,4,3-benzodioxaphosphepine (CAS82372-35-8) (0.88 mL, 3.67 mmol) in THF (25 mL) were stirred at RT for˜24 h. Hydrogen peroxide 35% (4.7 mL, 54.6 mmol) excess was added andthe mixture was stirred for 1 h. The solvent was removed under vacuumand the residue was quenched with sat. Na₂S₂O₃ and extracted with EtOAc.The organic layers were dried over MgSO₄. Auto-column (5 hexanes: 5EtOAc) gave a crude Intermediate 10 as a yellow oil ˜0.86 g.

Example 11 Compound 3(2S)-2-amino-3-({3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyldihydrogen phosphate

Intermediate 10 (0.86 g, 1.19 mmol) was treated with 10% Pd on C (0.30g) and hydrogen at 50 psi for 3 h. The mixture was filtered throughcelite. The filtrate was concentrated onto silica gel and purified withauto-column (gradient 0→100% MeOH in CH₂Cl₂) to give Compound 3 as asolid ˜50 mg.

(300 MHz, DMSO-d₆) δ: 8.10 (d, J=2.7, 1H), 7.70 (s, 1H), 7.47 (dd,J=2.1, 8.7, 1H), 7.27-7.14 (m, 6H), 6.99 (d, J=8.7, 1H), 6.85 (d, J=3.0,1H), 6.54 (dd, J=1.8, 3.6, 1H), 4.02 (t, J=6.3, 2H), 3.98-3.90 (m, 3H),2.58 (t, J=7.5, 2H), 1.84-1.78 (m, 2H), 1.67-1.62 (m, 2H), 1.52-1.44 (m,2H).

Compound 4 prepared from Intermediate 3 and the correspondingprocedure(s) as described for preparation of Intermediate 10 and inExample 11 for Compound 3. The results are tabulated below in Table 2.

TABLE 2 Compound 4 IUPAC Name(2S)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyl dihydrogen phosphate Structure

¹H NMR δ (ppm) (600 MHz, CF₃C(O)OD) δ: 7.68 (d, J = 3.0, 1H), 7.30-7.28(m, 1H), 7.25-7.22 (m, 3H), 7.20-7.16 (m, 3H), 7.14 (t, J = 7.2, 1H),7.10 (d, J = 9.0, 1H), 7.06 (d, J = 3.0, 1H), 5.02-4.97 (m, 2H),4.80-4.77 (m, 1H), 4.17 (t, J = 6.6, 2H), 2.65 (t, J = 7.2, 2H),1.96-1.92 (m, 2H), 1.75-1.70 (m, 2H), 1.59-1.56 (m, 2H). Intermediate 3

Biological Examples In Vitro Assay

Compounds were tested for S1P1 activity using the GTP γ³⁵S bindingassay. These compounds may be assessed for their ability to activate orblock activation of the human S1P1 receptor in cells stably expressingthe S1P1 receptor. GTP γ³⁵S binding was measured in the mediumcontaining (mM) HEPES 25, pH 7.4, MgCl₂ 10, NaCl 100, dithitothreitol0.5, digitonin 0.003%, 0.2 nM GTP γ³⁵S, and 5 μg membrane protein in avolume of 150 μl. Test compounds were included in the concentrationrange from 0.08 to 5,000 nM unless indicated otherwise. Membranes wereincubated with 100 μM 5′-adenylylimmidodiphosphate for 30 min, andsubsequently with 10 μM GDP for 10 min on ice. Drug solutions andmembrane were mixed, and then reactions were initiated by adding GTPγ³⁵S and continued for 30 min at 25° C. Reaction mixtures were filteredover Whatman GF/B filters under vacuum, and washed three times with 3 mLof ice-cold buffer (HEPES 25, pH7.4, MgCl₂ 10 and NaCl 100). Filterswere dried and mixed with scintillant, and counted for ³⁵S activityusing a β-counter. Agonist-induced GTP γ³⁵S binding was obtained bysubtracting that in the absence of agonist. Binding data were analyzedusing a non-linear regression method. In case of antagonist assay, thereaction mixture contained 10 nM S1P in the presence of test antagonistat concentrations ranging from 0.08 to 5000 nM.

Activity Potency:

S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀),

TABLE 3 S1P1 IUPAC name EC₅₀ (nM)(2R)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3- 96(2-thienyl)phenyl}amino)propyl dihydrogen phosphate(2S)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3- 34(2-thienyl)phenyl}amino)propyl dihydrogen phosphate(2S)-2-amino-3-({3-(2-furyl)-4-[(5-phenylpentyl)oxy] 8phenyl}amino)-3-oxopropyl dihydrogen phosphate(2S)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2- 3thienyl)phenyl}amino)propyl dihydrogen phosphateLymphopenia Assay in Mice

Test drugs are prepared in a solution containing 3% (w/v) 2-hydroxypropyl β-cyclodextrin (HPBCD) and 1% DMSO to a final concentration of 1mg/ml, and subcutaneously injected to female C57BL6 mice (CHARLESRIVERS) weighing 20-25 g at the dose of 10 mg/Kg. Blood samples areobtained by puncturing the submandibular skin with a Goldenrod animallancet at 24, 48, 72, and 96 hrs post drug application. Blood iscollected into microvettes (SARSTEDT) containing EDTA tripotassium salt.Lymphocytes in blood samples are counted using a HEMAVET MultispeciesHematology System, HEMAVET HV950FS (Drew Scientific Inc.). (Hale, J. etal Bioorg. & Med. Chem. Lett. 14 (2004) 3351).

A lymphopenia assay in mice; as previously described, was employed tomeasure the in vivo blood lymphocyte depletion after dosing with(25)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate. This S1P1 agonist is useful for S1P-relateddiseases and exemplified by the lymphopenia in vivo response. Test drug,(25)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate was prepared in a solution containing 3% (w/v)2-hydroxy propyl β-cyclodextrin (HPBCD) and 1% DMSO to a finalconcentration of 1 mg/ml, and subcutaneously injected to female C57BL6mice (CHARLES RIVERS) weighing 20-25 g at the dose of 10 mg/Kg. Bloodsamples were obtained by puncturing the submandibular skin with aGoldenrod animal lancet at different time intervals such as: 24, 48, 72,and 96 h post drug application. Blood was collected into microvettes(SARSTEDT) containing EDTA tripotassium salt. Lymphocytes in bloodsamples were counted using a HEMAVET Multispecies Hematology System,HEMAVET HV950FS (Drew Scientific Inc.). Results are shown in FIG. 1 thatdepicts lowered lymphocyte count after 24 hours (<1 number oflymphocytes 10³/μL blood).

What is claimed:
 1. A method of treating an immunosuppressant disorderassociated with the sphingosine-1-phosphate receptor modulation, whereinthe immunosuppressant disorder is selected from: rheumatoid arthritis,psoriasis, atherosclerosis, autoimmune uveitis, dry eye, inflammatorybowel diseases, atopic allergy, atopic dermatitis, contact dermatitis,multiple sclerosis, Sjogren's syndrome and organ transplant rejection,in a mammal in need thereof, which comprises administering to a mammalin need thereof, a pharmaceutical composition comprising atherapeutically effective amount of at least one compound represented byFormula I or a pharmaceutically acceptable salt thereof:

wherein: R¹ is N or C—R⁹; R² is substituted or unsubstitutedheterocycle, C₅₋₈ cycloalkenyl or C₆₋₁₀ aryl; R³ is O, N—R¹⁰, CH—R¹¹, S,—CR¹²═CR¹³—, —C≡C— or —C(O)—; R⁴ is H, C₅₋₈ cycloalkenyl, C₃₋₈cycloalkyl or substituted or unsubstituted C₆₋₁₀ aryl; R⁵ is H, halogen,—OC₁₋₃ alkyl, C₁₋₃ alkyl or hydroxyl; R⁶ is H, halogen, —OC₁₋₃ alkyl,C₁₋₃ alkyl or hydroxyl; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; L isCHR⁷, O, S, NR⁸ or —C(O)—; R⁷ is H, C₁₋₃ alkyl, —OC₁₋₃ alkyl, halogen,hydroxyl or NR⁹R¹⁰; R⁸ is H or C₁₋₃ alkyl; R⁹ is H, halogen or C₁₋₃alkyl; R¹⁰ is H or C₁₋₃ alkyl; R¹¹ is H or C₁₋₃ alkyl; R¹² is H or C₁₋₃alkyl; R¹³ is H or C₁₋₃ alkyl; Q¹ is —CR¹⁴R¹⁵—; R¹⁴ is H, halogen, orC₁₋₃ alkyl; R¹⁵ is H, halogen, or C₁₋₃ alkyl; m is 0, 1, 2 or 3;

“*” represents the point of attachment to the rest of the molecule; R¹⁸is NR⁹, O, or S; Q² is the same or independently —OPO₃H₂, carboxylicacid, —PO₃H₂, —S(O)₂OH, —

with the proviso that when R³ is O, N—R¹⁰, S, —CR¹²═CR¹³—, —C≡C— or—C(O)— and b is 0 or 1 then L is not O, S, NR⁸ or —C(O)—.
 2. The methodaccording to claim 1, wherein said compound is represented by Formula Iwherein: R² is selected from: furan, 2-furyl and 3-furyl derivatives;thiophene, 2-thienyl and 3-thienyl derivatives; pyrrole, oxazole,thiazole, pyrrolidine, pyrroline, imidazole, pyrazole, pyrazoline,isoxazole, isothiazole, pyrazolidine, imidazoline, thiazoline,oxazoline, dihydrothiophene, dihydrofuran, tetrazole, triazole,oxadiazole, 1,2,5-oxadiazole, thiadiazole, 1,2,3-triazole,1,2,4-triazole, pyrrolidinone, pyrrol-2(3H)-one, imidazolidin-2-one and1,2,4-triazol-5(4H).
 3. The method according to claim 1, wherein saidcompound is represented by Formula I wherein: R⁴ is phenyl with ortho,meta and para substitution with groups selected from: fluoro, chloro,bromo, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethoxy,trifluoromethyl, perfluorinated ethyl, perfluorinated propyl andperfluorinated isopropyl.
 4. The method according to claim 1, whereinsaid compound is represented by Formula I wherein: R³ is O.
 5. Themethod according to claim 1, wherein said compound is represented byFormula I wherein: R¹ is N.
 6. The method according to claim 1, whereinsaid compound is represented by Formula I wherein: R¹ is C—R⁹.
 7. Themethod according to claim 1, wherein said compound is represented byFormula I wherein: R¹ is C—R⁹; R² is five-membered substituted orunsubstituted heterocycle; R³ is O; R⁴ is substituted or unsubstitutedphenyl; R⁵ is H or halogen; R⁶ is H or halogen; a is 1 or 2; b is 1 or2; L is CHR⁷; R⁷ is H; R⁹ is H or C₁₋₃ alkyl; Q¹ is —CR¹⁴R¹⁵—; R¹⁴ is H;R¹⁵ is H; m is 2;

“*” represents the point of attachment to the rest of the molecule; R¹⁸is NR⁹; Q² is the same or independently —OPO₃H₂, carboxylic acid,—PO₃H₂, —P(O)MeOH, —P(O)(H)OH, or —OH.
 8. The method according to claim1, wherein said compound is represented by Formula I wherein: R¹ isC—R⁹; R² is five-membered substituted or unsubstituted heterocycle; R³is O; R⁴ is substituted or unsubstituted phenyl; R⁵ is H or F; R⁶ is Hor F; a is 1 or 2; b is 1 or 2; L is CHR⁷; R⁷ is H; R⁹ is H or C₁₋₃alkyl; Q¹ is —CR¹⁴R¹⁵—; R¹⁴ is H; R¹⁵ is H; m is 2;

“*” represents the point of attachment to the rest of the molecule; R¹⁸is NR⁹; Q² is the same or independently —OPO₃H₂, carboxylic acid,—PO₃H₂, —P(O)MeOH, —P(O)(H)OH, or —OH.
 9. The method according to claim1, wherein said compound is represented by Formula I wherein: R¹ isC—R⁹; R² is five-membered substituted or unsubstituted heterocycle; R³is O; R⁴ is substituted or unsubstituted phenyl; R⁵ is H or F; R⁶ is Hor F; a is 1 or 2; b is 1 or 2; L is CHR⁷; R⁷ is H; R⁹ is H or C₁₋₃alkyl; Q¹ is —CR¹⁴R¹⁵—; R¹⁴ is H; R¹⁵ is H; m is 2;

“*” represents the point of attachment to the rest of the molecule; Q²is the same or independently —OPO₃H₂, carboxylic acid, —PO₃H₂,—P(O)MeOH, —P(O)(H)OH, or —OH.
 10. The method according to claim 1,wherein said compound is represented by Formula I wherein: R¹ is C—R⁹;R² is substituted or unsubstituted heterocycle; R³ is O; R⁴ issubstituted or unsubstituted phenyl; R⁵ is H or halogen; R⁶ is H orhalogen; a is 2; b is 2; L is CHR⁷; R⁷ is H; R⁹ is H; m is 0; T is—NH-Q², “*” represents the point of attachment to the rest of themolecule; Q² is the same or independently —OPO₃H₂, carboxylic acid,—PO₃H₂, —S(O)₂OH,


11. The method according to claim 1, wherein said compound isrepresented by Formula I wherein: R¹ is C—R⁹; R² is substituted orunsubstituted heterocycle; R³ is O; R⁴ is substituted or unsubstitutedphenyl; R⁵ is H or F; R⁶ is H or F; a is 2; b is 2; L is CHR⁷; R⁷ is H;R⁹ is H; m is 0; T is —NH-Q², “*” represents the point of attachment tothe rest of the molecule; Q² is the same or independently —OPO₃H₂,carboxylic acid, —PO₃H₂, —S(O)₂OH,


12. The method according to claim 1, wherein said compound isrepresented by Formula I wherein: R¹ is C—R⁹; R² is substituted orunsubstituted heterocycle; R³ is O; R⁴ is substituted or unsubstitutedphenyl; R⁵ is H or F; R⁶ is H or F; a is 2; b is 2; L is CHR⁷; R⁷ is H;R⁹ is H; m is 0; T is —NH-Q², “*” represents the point of attachment tothe rest of the molecule; Q² is the same or independently —OPO₃H₂,carboxylic acid, —PO₃H₂, —S(O)₂OH,


13. The method according to claim 1, wherein said compound isrepresented by Formula I wherein: R¹ is C—R⁹; R² is substituted orunsubstituted heterocycle; R³ is O; R⁴ is substituted or unsubstitutedphenyl; R⁵ is H or F; R⁶ is H or F; a is 2; b is 2; L is CHR⁷; R⁷ is H;R⁹ is H; m is 0; T is —NH-Q², “*” represents the point of attachment tothe rest of the molecule; Q² is the same or independently —OPO₃H₂,carboxylic acid, —PO₃H₂, —S(O)₂OH,


14. The method according to claim 1, wherein said compound isrepresented by Formula I wherein: R¹ is C—R⁹; R² is substituted orunsubstituted heterocycle; R³ is O; R⁴ is substituted or unsubstitutedphenyl; R⁵ is H or F; R⁶ is H or F; a is 2; b is 2; L is CHR⁷; R⁷ is H;R⁹ is H; m is 0; T is —NH-Q², “*” represents the point of attachment tothe rest of the molecule; Q² is the same or independently —OPO₃H₂,carboxylic acid, —PO₃H₂, —S(O)₂OH,


15. The method according to claim 1, wherein the compound represented byFormula I is selected from:(2R)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate;(2S)-2-amino-2-methyl-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate;2-amino-3-hydroxy-2-methyl-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;2-amino-3-hydroxy-2-methyl-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;(2S)-2-amino-3-({3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyldihydrogen phosphate;(2S)-2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}amino)propyldihydrogen phosphate;2-amino-N-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;2-amino-3-hydroxy-N-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}propanamide;2-amino-3-({3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyldihydrogen phosphate;2-amino-3-{[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]amino}-3-oxopropyldihydrogen phosphate;2-amino-3-({3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}amino)-3-oxopropyldihydrogen phosphate;2-amino-3-oxo-3-({4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}amino)propyldihydrogen phosphate;2-amino-3-({6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}amino)-3-oxopropyldihydrogen phosphate;2-amino-N-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;2-amino-N-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;2-amino-N-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-3-hydroxypropanamide;2-amino-3-hydroxy-N-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}propanamide;2-amino-N-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-3-hydroxypropanamide;2-amino-4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyldihydrogen phosphate;2-amino-2-(hydroxymethyl)-4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}butyldihydrogen phosphate;2-amino-4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyldihydrogen phosphate;2-amino-4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-2-(hydroxymethyl)butyldihydrogen phosphate;2-amino-4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-2-(hydroxymethyl)butyldihydrogen phosphate;2-amino-2-(hydroxymethyl)-4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}butyldihydrogen phosphate;2-amino-4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-2-(hydroxymethyl)butyldihydrogen phosphate;2-amino-2-(2-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;2-amino-2-(2-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}ethyl)propane-1,3-diol;2-amino-2-(2-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;2-amino-2-{2-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]ethyl}propane-1,3-diol;2-amino-2-(2-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}ethyl)propane-1,3-diol;2-amino-2-(2-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}ethyl)propane-1,3-diol;2-amino-2-(2-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}ethyl)propane-1,3-diol;2-amino-2-(4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-(4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-{4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-1H-imidazol-2-yl}ethyldihydrogen phosphate;2-amino-2-(4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-(4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-1H-imidazol-2-yl)ethyldihydrogen phosphate;2-amino-2-(4-{3-(2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(2-thienyl)phenyl}-1H-imidazol-2-yl)ethanol;2-amino-2-(4-{3-(5-fluoro-2-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;2-amino-2-{4-[4-{[5-(4-fluorophenyl)pentyl]oxy}-3-(2-furyl)phenyl]-1H-imidazol-2-yl}ethanol;2-amino-2-(4-{3-(3-furyl)-4-[(5-phenylpentyl)oxy]phenyl}-1H-imidazol-2-yl)ethanol;2-amino-2-(4-{4-[(5-phenylpentyl)oxy]-3-(3-thienyl)phenyl}-1H-imidazol-2-yl)ethanol;and2-amino-2-(4-{6-(2-furyl)-5-[(5-phenylpentyl)oxy]pyridin-2-yl}-1H-imidazol-2-yl)ethanol.